According to the American Foundation for Urologic Disease, over 17 million Americans suffer from overactive bladder. Incontinence is particularly common in the elderly and is present in approximately fifty percent of nursing home patients. Further, urinary incontinence affects nearly all women in some form during their lifetime and is of significant medical and social concern to those who experience the affliction.
Urinary incontinence arises from the anatomy and the physiology of the urinary tract, which is composed of a bladder and a sphincter. Anatomically, the bladder consists of the bladder musculature known as detrusor and the trigone. The sphincter includes the bladder neck and the proximal urethra. The detrusor muscle is innervated by the pelvic nerve through the parasympathetic nervous system, and the bladder neck and proximal urethra are innervated by the sympathetic nervous system (See, “Chapter 215-Urinary Incontinence,” The Merck Manual, 17th Ed., M. H. Beers and R. Berkow, eds., Merck Research Laboratories, Whitehouse Station, N.J., 1999, pp. 1816-1824).
The major functions of the bladder are the storage and expulsion of urine. The bladder is responsible for accommodating increasing volumes of urine at low pressures. Normally, the bladder remains closed during bladder filling and continence is maintained as long as the bladder neck and urethral pressure exceeds intravesical pressure. Voluntary voiding occurs when intravesical pressure exceeds bladder neck and urethral pressure, and involuntary voiding, also known as involuntary incontinence, occurs when the travesical pressure exceeds the bladder neck and urethral pressure. Involuntary incontinence, also known as urge incontinence and overactive bladder, occurs with a loss of a large volume of urine accompanied by symptoms of urgency, frequency and nocturia caused by an unstable bladder or detrusor instability. The patient may lose urine with a change in position or with auditory stimulation. The loss of small volumes of urine usually occurs because of bladder over-distension by a large amount of residual urine; this condition is referred to as overflow incontinence. Urinary incontinence is also known as overactive bladder, which exhibits symptoms of urinary frequency or urge incontinence.
Incontinence can be caused by a variety of factors including pregnancy, estrogen deficiency, general weakening of the sphincter or pelvic floor muscles, surgery along the urinary tract, infection and other maladies localized in the urinary tract. Several types of incontinence including stress incontinence, urge incontinence, and total incontinence exist. Stress incontinence occurs under physical stress and individuals suffering from this type of incontinence might experience symptoms resulting in urine discharge during physically stressful events. Examples of stressful events include coughing, laughing, sneezing, and rigorous exercise. Symptoms of urge incontinence are characterized by an urgent desire to urinate and can result in total discharge of the bladder. This type of incontinence can occur at any time, but frequently occurs when a person has a sudden change in their physical position. Total incontinence is characterized by a total lack of control over urine discharge and is frequently caused by a complete failure of the sphincter muscles.
Urinary incontinence is an unwanted side effect associated with administration of a number of therapeutic drugs such as diuretics (e.g., furosemide and bumetamide), anticholinergics (e.g., antihistamines and benztropine), psychoactive drugs such as tricyclic antidepressants, antipsychotics, opioids, calcium-channel blockers, vincristine and ACE inhibitors (e.g., captopril) (Merck Manual, ibid., p. 1816).
Current treatments for incontinence include protective underwear such as diapers or a urinary catheter that collects discharged urine. These types of treatments can be uncomfortable, unsightly, and socially awkward. Pelvic exercises are also used to strengthen weak pelvic muscles. However, such exercises have limited affect, especially if the person does not perform the exercises properly or on a regular basis. Additionally, surgery is often performed to tighten the sphincter muscles. Surgery is a rather severe, and possibly dangerous, treatment and is typically performed as a last resort if all other treatments fail.
Drug therapy is an alternative treatment for incontinence. The type of drug that is used can vary depending on the type and cause of incontinence. For example, menopausal and post-menopausal women often experience estrogen deficiency, which causes a variety of symptoms including a thinning of the urethral and vaginal mucosa. Thinning of the urethral mucosa can result in a lack of urethral pressure and thus induce stress incontinence. Estrogen replacement therapy may help control menopause-related incontinence because some of the estrogen will reach and stimulate estrogen receptors in the urethral wall. Stimulation of estrogen receptors triggers an increase in the thickness of the urethral mucosa, which increases urethral pressure and helps to control incontinence (Merkerj, So. Medical J. 2001 (94:10) 952-957).
In practice, estrogen is administered vaginally, orally, or transdermally. These forms of administration can cause serious side effects because normal and healthy tissue outside the urinary tract, which is the desired treatment area, are exposed to estrogen. Examples of possible side effects include breast tenderness, vaginal bleeding, cancer such as endometrial carcinoma, susceptibility to hypertension and risk of abnormal blood clotting. The risk of side effects is even greater if sustained use of estrogen occurs over a prolonged period. Therefore, estrogen administration may be unwarranted if the main goal of therapy is to treat incontinence.
Other agents that increase the tone of the internal and external sphincter muscles may be used to treat incontinence. Examples of these agents include sympathomimetics such as α-adrenergic agonists and nicotinic cholinergic agonists. However, current methods of delivering these agents have problems similar to the method for delivering estrogen. Areas outside the urinary tract are exposed to the agent, which increases the risk of side effects. For example, sympathomimetics can result in elevated blood pressure, stimulation of the central nervous system resulting in insomnia and anxiety, dizziness, tremors, and cardiac arrhythmias. Nicotinic cholinergic agonists can also have harmful effects because there are nicotinic cholinergic receptors in the skeletal muscles, autonomic ganglia and the adrenal medulla. Thus, treatment using nicotinic cholinergic agonists can also cause a variety of side effects.
The γ-aminobutyric acid (γ-aminobutyric acid is abbreviated herein as “GABA”) analog gabapentin (1) has been approved in the United States for the treatment of epileptic seizures and post-herpetic neuralgia. The drug has also shown efficacy in controlled studies for treating neuropathic pain of varying etiologies. Gabapentin has been used to treat a number of other medical disorders (Magnus, Epilepsia 1999, 40, S66-72).

The broad pharmaceutical activities of GABA analogs such as gabapentin has stimulated intensive interest in preparing related compounds that have superior pharmaceutical properties in comparison to GABA, e.g., the ability to cross the blood brain barrier (see, e.g., Satzinger et al., U.S. Pat. No. 4,024,175; Silverman et al., U.S. Pat. No. 5,563,175; Horwell et al., U.S. Pat. No. 6,020,370; Silverman et al., U.S. Pat. No. 6,028,214; Horwell et al., U.S. Pat. No. 6,103,932; Silverman et al., U.S. Pat. No. 6,117,906; Silverman, International Publication No. WO 92/09560; Silverman et al., International Publication No. WO 93/23383; Horwell et al., International Publication No. WO 97/29101, Horwell et al., International Publication No. WO 97/33858; Horwell et al., International Publication No. WO 97/33859; Bryans et al., International Publication No. WO 98/17627; Guglietta et al., International Publication No. WO 99/08671; Bryans et al., International Publication No. WO 99/21824; Bryans et al., International Publication No. WO 99/31057; Belliotti et al., International Publication No. WO 99/31074; Bryans et al., International Publication No. WO 99/31075; Bryans et al., International Publication No. WO 99/61424; Bryans et al., International Publication No. WO 00/15611; Bellioti et al., International Publication No. WO 00/31020; Bryans et al., International Publication No. WO 00/50027; and Bryans et al., International Publication No. WO 02/00209). One analog of particular interest is pregabalin (2), which may possess greater potency in pre-clinical models of pain and epilepsy than gabapentin. GABA analogs such as gabapentin and pregabalin have been used to treat urinary incontinence (Segal et al., International Publication No. WO 00/61135). Prodrugs of GABA analogs such as gabapentin and pregabalin have also been used to treat patients who frequently urinate but who do not have urinary incontinence or involuntary loss of urine (Thor et al., U.S. Patent Publication No. 2004/0142034).
Although the mechanism of action of gabapentin in modulating these aforementioned disease states (including urinary incontinence) is not understood with certainty, gabapentin, pregabalin and related analogs are known to interact with the α2δ subunit of neuronal voltage-gated calcium channels (Gee et al., J. Biol. Chem. 1996, 271, 5768-5776; Bryans et al., J. Med. Chem. 1998, 41, 1838-1845). Methods of administering compounds such as GABA analogs (e.g., gabapentin, pregabalin, etc.) to a patient which modulate α2δ subunits of voltage-gated calcium channels have been described (Guttuso, U.S. Pat. No. 6,310,098; Thor et al., supra).
One significant problem associated with the clinical use of many GABA analogs, including gabapentin and pregabalin, is rapid systemic clearance. Consequently, these drugs require frequent dosing to maintain a therapeutic or prophylactic concentration in the systemic circulation (Bryans et al., Med. Res. Rev. 1999, 19, 149-177). For example, dosing regimens of 300-600 mg doses of gabapentin administered three times per day are typically used for anticonvulsive therapy. Higher doses (1800-3600 mg/day in three or four divided doses) are typically used for the treatment of neuropathic pain states.
Although oral sustained released formulations are conventionally used to reduce the dosing frequency of drugs that exhibit rapid systemic clearance, oral sustained release formulations of gabapentin and pregabalin have not been developed because these drugs not absorbed via the large intestine. Rather, these compounds are typically absorbed in the small intestine by one or more amino acid transporters (e.g., the “large neutral amino acid transporter,” see Jezyk et al., Pharm. Res. 1999, 16, 519-526). The limited residence time of both conventional and sustained release oral dosage forms in the proximal absorptive region of the gastrointestinal tract necessitates frequent daily dosing of conventional oral dosage forms of these drugs, and has prevented the successful application of sustained release technologies to many GABA analogs.
One method for overcoming rapid systemic clearance of GABA analogs relies upon the administration of an extended release dosage formulation containing a GABA analog prodrug (Gallop et al., International Publication Nos. WO 02/100347 and WO 02/100349). Such prodrugs may be absorbed over wider regions of the gastrointestinal tract than the parent drug, and across the wall of the colon where sustained release oral dosage forms typically spend a significant portion of gastrointestinal transit time. These prodrugs are converted to the parent GABA analog upon absorption in vivo.
Current delivery techniques expose tissue outside of the desired treatment area (i.e., the urinary tract), to incontinence agents which inefficiently uses the agents and dramatically increases the risk of side effects. Therefore, there is a need in the art for a method of delivering an agent such as a prodrug of a GABA analog, particularly in extended release dosage form, which can treat and/or prevent incontinence with a reduced risk of side effects.